Plant phenolic antioxidants related to the 3, 4-dihydroxycinammic acid exhibit potent antitumor activities, including anti-proliferative, anti-mitogenic and anti-angiogenic properties. Two structurally-related members of this family, Caffeic Acid Phenethyl Ester (CAPE) and curcumin, have been shown to preferentially induce apoptosis in transformed but not untransformed cells in vitro, and to inhibit polyp formation in experimental mouse tumor models with little or no overt toxicity. The anti-tumorigenic activity of CAPE and curcumin have been attributed to their antioxidant properties and their ability to inhibit the Nuclear Factor Kappa-B/COX-2 pathway. In preliminary studies, the PI has shown that CAPE and curcumin inhibit activation of the protooncogene kinase, Akt/PKB, that lies upstream of NF-kB activation. Akt is abnormally activated in a variety of tumors and promotes cell survival, cell proliferation and angiogenesis. The PI also has shown that CAPE exhibits potent radio- and chemosensitization properties against colorectal carcinoma cells. Since the Akt pathway is associated with resistance to ionizing radiation and increased angiogenesis, the PI proposes that CAPE and curcumin will be useful radiosensitizing, chemosensitizing, and anti-angiogenic agents for the treatment of solid tumors. In Aim 1, the preliminary studies in colorectal carcinoma cells will be extended to brain and prostate cell lines and tumor xenografts. Aim 2 will address whether the Akt signalling pathway or other anti-apoptotic pathways are the primary targets for CAPE and curcumin radiosensitization. In Aim 3, the role of increased oxidative stress induced preferentially in transformed cells by CAPE and curcumin will be evaluated as a potential radiosensitization mechanism. Aim 4 will extend the studies in Alms 1-3 to animal models of tumor radiosensitization and normal tissue injury to examine the ability of CAPE and curcumin to induce in vivo tumor radiosensitization and protect normal tissues fro radiation injury. Results from these studies will establish the molecular basis for the demonstrated radio/chemosensitizing properties of this class of naturally occurring compounds and will also set the stage for the design of clinical trials using CAPE and/or curcumin as chemotherapeutic agents and radiation dose modifiers.